RAPGEF3

Last updated
RAPGEF3
Identifiers
Aliases RAPGEF3 , CAMP-GEFI, EPAC, EPAC1, HSU79275, bcm910, Rap guanine nucleotide exchange factor 3
External IDs OMIM: 606057; MGI: 2441741; HomoloGene: 21231; GeneCards: RAPGEF3; OMA:RAPGEF3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10411

223864

Ensembl

ENSG00000079337

ENSMUSG00000022469

UniProt

O95398

Q8VCC8

RefSeq (mRNA)

NM_001098531
NM_001098532
NM_006105

NM_001177810
NM_001177811
NM_144850
NM_001357630

RefSeq (protein)

NP_001092001
NP_001092002
NP_006096

NP_001171281
NP_001171282
NP_659099
NP_001344559

Location (UCSC) Chr 12: 47.73 – 47.77 Mb Chr 15: 97.74 – 97.77 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Rap guanine nucleotide exchange factor 3 also known as exchange factor directly activated by cAMP 1 (EPAC1) or cAMP-regulated guanine nucleotide exchange factor I (cAMP-GEFI) is a protein that in humans is encoded by the RAPGEF3 gene. [5] [6] [7]

Contents

As the name suggests, EPAC proteins (EPAC1 and EPAC2) are a family of intracellular sensors for cAMP, and function as nucleotide exchange factors for the Rap subfamily of RAS-like small GTPases.

History and discovery

Since the landmark discovery of the prototypic second messenger cAMP in 1957, three families of eukaryotic cAMP receptors have been identified to mediate the intracellular functions of cAMP. While protein kinase A (PKA) or cAMP-dependent protein kinase and cyclic nucleotide regulated ion channel (CNG and HCN) were initially unveiled in 1968 and 1985 respectively; EPAC genes were discovered in 1998 independently by two research groups. Kawasaki et al. identified cAMP-GEFI and cAMP-GEFII as novel genes enriched in brain using a differential display protocol and by screening clones with cAMP-binding motif. [7] De Rooij and colleagues performed a database search for proteins with sequence homology to both GEFs for Ras and Rap1 and to cAMP-binding sites, which led to the identification and subsequent cloning of RAPGEF3 gene. [6] The discovery of EPAC family cAMP sensors suggests that the complexity and possible readouts of cAMP signaling are much more elaborate than previously envisioned. This is due to the fact that the net physiological effects of cAMP entail the integration of EPAC- and PKA-dependent pathways, which may act independently, converge synergistically, or oppose each other in regulating a specific cellular function. [8] [9] [10]

Gene

Human RAPGEF3 gene is present on chromosome 12 (12q13.11: 47,734,367-47,771,041). [11] Out of the many predicted transcript variants, three that are validated in the NCBI database include transcript variant 1 (6,239 bp), 2 (5,773 bp) and 3 (6,003 bp). While variant 1 encodes for EPAC1a (923 amino acids), both variant 2 and 3 encode EPAC1b (881 amino acids). [5]

Protein family

In mammals, the EPAC protein family contains two members: EPAC1 (this protein) and EPAC2 ( RAPGEF4 ). They further belong to a more extended family of Rap/Ras-specific GEF proteins that also include C3G ( RAPGEF1 ), PDZ-GEF1 ( RAPGEF2 ), PDZ-GEF2 ( RAPGEF6 ), Repac ( RAPGEF5 ), CalDAG-GEF1 ( ARHGEF1 ), CalDAG-GEF3 ( ARHGEF3 ), PLCε1 ( PLCE1 ) and RasGEF1A, B, C.

Protein structure and mechanism of activation

EPAC proteins consist of two structural lobes/halves connected by the so-called central “switchboard” region. [12] The N terminal regulatory lobe is responsible for cAMP binding while the C-terminal lobe contains the nucleotide exchange factor activity. At the basal cAMP-free state, EPAC is kept in an auto-inhibitory conformation, in which the N-terminal lobe folds on top of the C-terminal lobe, blocking the active site. [13] [14] Binding of cAMP to EPAC induces a hinge motion between the regulatory and catalytic halves. As a consequence, the regulatory lobe moves away from catalytic lobe, freeing the active site. [15] [16] In addition, cAMP also prompts conformational changes within the regulatory lobe that lead to the exposure of a lipid binding motif, allowing the proper targeting of EPAC1 to the plasma membrane. [17] [18] Entropically favorable changes in protein dynamics have also been implicated in cAMP mediated EPAC activation. [19] [20]

Tissue distribution and cellular localization

Human and mice EPAC1 mRNA expression is rather ubiquitous. As per Human Protein Atlas documentation, EPAC1 mRNA is detectable in all normal human tissues. Further, medium to high levels of corresponding protein are also measureable in more than 50% of the 80 tissue samples analyzed. [21] In mice, high levels of EPAC1 mRNA are detected in kidney, ovary, skeletal muscle, thyroid and certain areas of the brain. [7]

EPAC1 is a multifunctional protein whose cellular functions are tightly regulated in spatial and temporal manners. EPAC1 is localized to various subcellular locations during different stages of the cell cycle. [22] Through interactions with an array of cellular partners, EPAC1 has been shown to form discrete signalsomes at plasma membrane, [18] [23] [24] [25] nuclear-envelope, [26] [27] [28] and cytoskeleton, [29] [30] [31] where EPAC1 regulates numerous cellular functions.

Clinical relevance

Studies based on genetically engineered mouse models of EPAC1 have provided valuable insights into understanding the in vivo functions of EPAC1 under both physiological and pathophysiological conditions. Overall, mice deficient of EPAC1 or both EPAC1 and EPAC2 appear relatively normal without major phenotypic defects. These observations are consistent with the fact that cAMP is a major stress response signal not essential for survival. This makes EPAC1 an attractive target for therapeutic intervention as the on-target toxicity of EPAC-based therapeutics will likely be low. Up to date, genetic and pharmacological analyses of EPAC1 in mice have revealed that EPAC1 plays important roles in cardiac stresses and heart failure, [32] [33] leptin resistance and energy homeostasis, [34] [35] [36] chronic pain, [37] [38] infection, [39] [40] cancer metastasis, [41] metabolism [42] and secondary hemostasis. [43] Interestingly, EPAC1 deficient mice have prolonged clotting time and fewer, younger, larger and more agonist-responsive blood platelets. EPAC1 is not present in mature platelets, but is required for normal megakaryopoiesis and the subsequent expression of several important proteins involved in key platelets functions. [43]

Pharmacological agonists and antagonists

There have been significant interests in discovering and developing small modulators specific for EPAC proteins for better understanding the functions of EPAC mediated cAMP signaling, as well as for exploring the therapeutic potential of targeting EPAC proteins. Structure-based design targeting the key difference between the cAMP binding sites of EPAC and PKA led to the identification of a cAMP analogue, 8-pCPT-2’-O-Me-cAMP that is capable of selectively activate EPAC1. [44] [45] Further modifications allowed the development of more membrane permeable and metabolically stable EPAC-specific agonists. [46] [47] [48] [49]

A high throughput screening effort resulted in the discovery of several novel EPAC specific inhibitors (ESIs), [50] [51] [52] among which two ESIs act as EPAC2 selective antagonists with negligible activity towards EPAC1. [51] Another ESI, CE3F4, with modest selectivity for EPAC1 over EPAC2, has also been reported. [53] The discovery of EPAC specific antagonists represents a research milestone that allows the pharmacological manipulation of EPAC activity. In particular, one EPAC antagonist, ESI-09, with excellent activity and minimal toxicity in vivo, has been shown to be a useful pharmacological tool for probing physiological functions of EPAC proteins and for testing therapeutic potential of targeting EPAC in animal disease models. [39] [41] [54]

Notes

Related Research Articles

<span class="mw-page-title-main">Cyclic adenosine monophosphate</span> Cellular second messenger

Cyclic adenosine monophosphate is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway.

<span class="mw-page-title-main">Cyclic nucleotide</span> Cyclic nucleic acid

A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, and a single phosphate group. As can be seen in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.

<span class="mw-page-title-main">Nucleotide exchange factor</span>

Nucleotide exchange factors (NEFs) are proteins that stimulate the exchange (replacement) of nucleoside diphosphates for nucleoside triphosphates bound to other proteins.

<span class="mw-page-title-main">CREB1</span> Mammalian protein found in Homo sapiens

CAMP responsive element binding protein 1, also known as CREB-1, is a protein that in humans is encoded by the CREB1 gene. This protein binds the cAMP response element, a DNA nucleotide sequence present in many viral and cellular promoters. The binding of CREB1 stimulates transcription.

<span class="mw-page-title-main">ATF1</span> Protein-coding gene in humans

Cyclic AMP-dependent transcription factor ATF-1 is a protein that in humans is encoded by the ATF1 gene.

<span class="mw-page-title-main">RAP2A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rap-2a is a protein that in humans is encoded by the RAP2A gene. RAP2A is a member of the Ras-related protein family.

<span class="mw-page-title-main">HCN2</span> Protein-coding gene in the species Homo sapiens

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2 is a protein that in humans is encoded by the HCN2 gene.

<span class="mw-page-title-main">RAPGEF4</span> Protein-coding gene in the species Homo sapiens

Rap guanine nucleotide exchange factor (GEF) 4 (RAPGEF4), also known as exchange protein directly activated by cAMP 2 (EPAC2) is a protein that in humans is encoded by the RAPGEF4 gene.

<span class="mw-page-title-main">RAP2B</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rap-2b is a protein that in humans is encoded by the RAP2B gene. RAP2B belongs to the Ras-related protein family.

<span class="mw-page-title-main">MTG1</span> Protein-coding gene in the species Homo sapiens

Mitochondrial GTPase 1 is an enzyme that in humans is encoded by the MTG1 gene.

<span class="mw-page-title-main">HCN1</span> Protein-coding gene in the species Homo sapiens

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 is a protein that in humans is encoded by the HCN1 gene.

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are integral membrane proteins that serve as nonselective voltage-gated cation channels in the plasma membranes of heart and brain cells. HCN channels are sometimes referred to as pacemaker channels because they help to generate rhythmic activity within groups of heart and brain cells. HCN channels are activated by membrane hyperpolarization, are permeable to Na + and K +, and are constitutively open at voltages near the resting membrane potential. HCN channels are encoded by four genes and are widely expressed throughout the heart and the central nervous system.

<span class="mw-page-title-main">RAPGEF2</span> Protein-coding gene in the species Homo sapiens

Rap guanine nucleotide exchange factor 2 is a protein that in humans is encoded by the RAPGEF2 gene.

<span class="mw-page-title-main">RASGRP2</span> Protein-coding gene in the species Homo sapiens

RAS guanyl-releasing protein 2 is a protein that in humans is encoded by the RASGRP2 gene.

<span class="mw-page-title-main">Cyclic nucleotide-gated channel alpha 2</span> Protein-coding gene in humans

Cyclic nucleotide gated channel alpha 2, also known as CNGA2, is a human gene encoding an ion channel protein.

<span class="mw-page-title-main">RAP1GDS1</span> Protein-coding gene in the species Homo sapiens

Rap1 GTPase-GDP dissociation stimulator 1 is an enzyme that in humans is encoded by the RAP1GDS1 gene.

<span class="mw-page-title-main">HCN3</span> Protein-coding gene in the species Homo sapiens

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 is a protein that in humans is encoded by the HCN3 gene.

<span class="mw-page-title-main">RAPGEF5</span> Protein-coding gene in the species Homo sapiens

Rap guanine nucleotide exchange factor 5 is a protein that in humans is encoded by the RAPGEF5 gene.

In the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication.

<span class="mw-page-title-main">Cyclic di-AMP</span> Chemical compound

Cyclic di-AMP is a second messenger used in signal transduction in bacteria and archaea. It is present in many Gram-positive bacteria, some Gram-negative species, and archaea of the phylum Euryarchaeota.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022469 – Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  39. 1 2 Gong B, Shelite T, Mei FC, Ha T, Hu Y, Xu G, et al. (November 2013). "Exchange protein directly activated by cAMP plays a critical role in bacterial invasion during fatal rickettsioses". Proceedings of the National Academy of Sciences of the United States of America. 110 (48): 19615–20. Bibcode:2013PNAS..11019615G. doi: 10.1073/pnas.1314400110 . PMC   3845138 . PMID   24218580.
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  45. ↑ Christensen AE, Selheim F, de Rooij J, Dremier S, Schwede F, Dao KK, et al. (September 2003). "cAMP analog mapping of Epac1 and cAMP kinase. Discriminating analogs demonstrate that Epac and cAMP kinase act synergistically to promote PC-12 cell neurite extension". The Journal of Biological Chemistry. 278 (37): 35394–402. doi: 10.1074/jbc.M302179200 . PMID   12819211.
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